Obesity as a pleiotropic effect of gene action

Abstract

Obesity, an easily detected and quantifiable phenotypic endpoint, is often considered, colloquially, as a disease. However, the study of obesity in rodents suggests that it is merely a convenient indicator of diverse underlying metabolic and physiologic dysregulations, rather than a disease entity in itself. To illustrate this concept, the differences between the murine Lep(ob)/Lep(ob) and A(vy)/- 'obesity' syndromes are delineated. In both syndromes, pleiotropic effects of single mutations play a major role in altering the homeostatic regulation of energy metabolism and a myriad of extra- and intracellular processes in a diversity of tissues and cell types. The Lep(ob)/Lep(ob) syndrome mimics juvenile-onset obesity, whereas the A(vy)/- syndrome resembles maturity-onset obesity. The A(vy)/- syndrome has its basis in overabundance of agouti protein, whereas the Lep(ob)/Lep(ob) syndrome results from a lack of active leptin hormone. Lep(ob)/Lep(ob) mice have a smaller lean body mass whereas A(vy)/- mice nave a larger lean body mass than their respective lean siblings. Lep(ob)/Lep(ob) mice have fewer tung and mammary tumors than their lean Lep/- littermates, and A(vy)/- develop more mammary and lung tumors than their lean A/- or a/a siblings. Lep(ob)/Lap(ob) mice are infertile or sterile whereas A(vy)/- mice are fertile. Thus, although adult Lep(ob)/Lep(ob) and A(vy)/- mice are both obese, many of the other morphologic and physiologic attributes of one mutant are diametrically opposite to those of the other.